JP6418949B2 - イミダゾ[1,2−b]ピリダジン系化合物、それを含む組成物、及びそれらを使用する方法 - Google Patents
イミダゾ[1,2−b]ピリダジン系化合物、それを含む組成物、及びそれらを使用する方法 Download PDFInfo
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- JP6418949B2 JP6418949B2 JP2014561020A JP2014561020A JP6418949B2 JP 6418949 B2 JP6418949 B2 JP 6418949B2 JP 2014561020 A JP2014561020 A JP 2014561020A JP 2014561020 A JP2014561020 A JP 2014561020A JP 6418949 B2 JP6418949 B2 JP 6418949B2
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- Prior art keywords
- mmol
- imidazo
- pyridazin
- esi
- nmr
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 46
- 239000000203 mixture Substances 0.000 title description 210
- 150000004942 imidazo[1,2-b]pyridazines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 241
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 61
- 125000005843 halogen group Chemical group 0.000 claims description 52
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 45
- 238000006467 substitution reaction Methods 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 208000004296 neuralgia Diseases 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 459
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 264
- 238000005481 NMR spectroscopy Methods 0.000 description 255
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 166
- 230000015572 biosynthetic process Effects 0.000 description 165
- 235000019439 ethyl acetate Nutrition 0.000 description 163
- 238000003786 synthesis reaction Methods 0.000 description 162
- -1 cycloalkenylalkyl Chemical group 0.000 description 156
- 238000006243 chemical reaction Methods 0.000 description 142
- 239000000243 solution Substances 0.000 description 136
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 106
- 239000007787 solid Substances 0.000 description 104
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 97
- 239000000047 product Substances 0.000 description 94
- 239000003921 oil Substances 0.000 description 90
- 235000019198 oils Nutrition 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
- 239000012267 brine Substances 0.000 description 79
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 79
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000000843 powder Substances 0.000 description 62
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 57
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 53
- 238000003756 stirring Methods 0.000 description 53
- 238000002953 preparative HPLC Methods 0.000 description 50
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 48
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- 239000011541 reaction mixture Substances 0.000 description 46
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 45
- 239000000284 extract Substances 0.000 description 44
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
- 238000013459 approach Methods 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- 239000000706 filtrate Substances 0.000 description 37
- 239000010410 layer Substances 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
- 238000004007 reversed phase HPLC Methods 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- 239000012071 phase Substances 0.000 description 32
- 239000000741 silica gel Substances 0.000 description 31
- 229910002027 silica gel Inorganic materials 0.000 description 31
- 238000010992 reflux Methods 0.000 description 30
- 239000000725 suspension Substances 0.000 description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 28
- 238000006069 Suzuki reaction reaction Methods 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- ZWTGQNADSJRPIB-UHFFFAOYSA-N 3-bromo-6-fluoroimidazo[1,2-b]pyridazine Chemical class N1=C(F)C=CC2=NC=C(Br)N21 ZWTGQNADSJRPIB-UHFFFAOYSA-N 0.000 description 24
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 24
- 238000001914 filtration Methods 0.000 description 23
- 230000007935 neutral effect Effects 0.000 description 23
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 20
- OYYSHVCYICCZID-UHFFFAOYSA-N 3-bromo-n-butylimidazo[1,2-b]pyridazin-6-amine Chemical compound N1=C(NCCCC)C=CC2=NC=C(Br)N21 OYYSHVCYICCZID-UHFFFAOYSA-N 0.000 description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 19
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 19
- PFHPKMPWBFJZEY-UHFFFAOYSA-N 3-bromo-6-chloroimidazo[1,2-b]pyridazine Chemical compound N1=C(Cl)C=CC2=NC=C(Br)N21 PFHPKMPWBFJZEY-UHFFFAOYSA-N 0.000 description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 125000004942 pyridazin-6-yl group Chemical group N1=NC=CC=C1* 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 208000002193 Pain Diseases 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 13
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 13
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 13
- 229910000160 potassium phosphate Inorganic materials 0.000 description 13
- 235000011009 potassium phosphates Nutrition 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 201000000980 schizophrenia Diseases 0.000 description 12
- HUZNRXFJHYNUMV-UHFFFAOYSA-N [4-(aminomethyl)phenyl]boronic acid;hydron;chloride Chemical compound Cl.NCC1=CC=C(B(O)O)C=C1 HUZNRXFJHYNUMV-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 102100037483 POU domain, class 6, transcription factor 1 Human genes 0.000 description 9
- 101710196406 POU domain, class 6, transcription factor 1 Proteins 0.000 description 9
- 239000012346 acetyl chloride Substances 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- 125000006309 butyl amino group Chemical group 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- GCLKFIQILCZTJK-UHFFFAOYSA-N propan-2-yl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)C)CCN1C1=NN2C(Br)=CN=C2C=C1 GCLKFIQILCZTJK-UHFFFAOYSA-N 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- CQXPAWKLNDTCJJ-UHFFFAOYSA-N (3-methoxypyridin-4-yl)boronic acid;hydrate Chemical compound O.COC1=CN=CC=C1B(O)O CQXPAWKLNDTCJJ-UHFFFAOYSA-N 0.000 description 8
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- DCNMATSPQKWETQ-UHFFFAOYSA-N (5-acetylthiophen-2-yl)boronic acid Chemical compound CC(=O)C1=CC=C(B(O)O)S1 DCNMATSPQKWETQ-UHFFFAOYSA-N 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 7
- 101150003085 Pdcl gene Proteins 0.000 description 7
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 101150118144 aak-1 gene Proteins 0.000 description 7
- 150000001499 aryl bromides Chemical group 0.000 description 7
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 235000017168 chlorine Nutrition 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- BJDBOCIEMFFURV-UHFFFAOYSA-N 4-[6-(butylamino)imidazo[1,2-b]pyridazin-3-yl]benzoic acid Chemical compound N12N=C(NCCCC)C=CC2=NC=C1C1=CC=C(C(O)=O)C=C1 BJDBOCIEMFFURV-UHFFFAOYSA-N 0.000 description 6
- URQYCXJSMFGDRO-UHFFFAOYSA-N 6-fluoroimidazo[1,2-b]pyridazine Chemical compound N1=C(F)C=CC2=NC=CN21 URQYCXJSMFGDRO-UHFFFAOYSA-N 0.000 description 6
- 0 CC1=C*C2=CC=C(C)**12 Chemical compound CC1=C*C2=CC=C(C)**12 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 239000006180 TBST buffer Substances 0.000 description 6
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 208000037765 diseases and disorders Diseases 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 6
- BFBHGYIZJKAGMU-NSHDSACASA-N propan-2-yl n-[(3s)-1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl]-n-methylcarbamate Chemical compound C1[C@@H](N(C)C(=O)OC(C)C)CCN1C1=NN2C(Br)=CN=C2C=C1 BFBHGYIZJKAGMU-NSHDSACASA-N 0.000 description 6
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- PNQYAMWGTGWJDW-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)-n-methylcarbamate Chemical compound NCCCN(C)C(=O)OC(C)(C)C PNQYAMWGTGWJDW-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 5
- NVOLYUXUHWBCRJ-UHFFFAOYSA-N (2-methoxypyridin-3-yl)boronic acid Chemical compound COC1=NC=CC=C1B(O)O NVOLYUXUHWBCRJ-UHFFFAOYSA-N 0.000 description 5
- GNRHNKBJNUVWFZ-UHFFFAOYSA-N (4-carbamoylphenyl)boronic acid Chemical compound NC(=O)C1=CC=C(B(O)O)C=C1 GNRHNKBJNUVWFZ-UHFFFAOYSA-N 0.000 description 5
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- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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US201261608758P | 2012-03-09 | 2012-03-09 | |
US61/608,758 | 2012-03-09 | ||
PCT/US2013/029043 WO2013134219A1 (fr) | 2012-03-09 | 2013-03-05 | Composés à base d'imidazo [1, 2-b] pyridazine, compositions les comprenant et utilisations de ceux-ci |
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JP2015509534A JP2015509534A (ja) | 2015-03-30 |
JP2015509534A5 JP2015509534A5 (fr) | 2016-04-14 |
JP6418949B2 true JP6418949B2 (ja) | 2018-11-07 |
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US (3) | US8969565B2 (fr) |
EP (1) | EP2822559B1 (fr) |
JP (1) | JP6418949B2 (fr) |
KR (1) | KR102085121B1 (fr) |
CN (1) | CN104470523B (fr) |
AR (1) | AR090291A1 (fr) |
AU (1) | AU2013230119B2 (fr) |
BR (1) | BR112014022271B1 (fr) |
CA (1) | CA2866164C (fr) |
ES (1) | ES2676826T3 (fr) |
HK (1) | HK1203407A1 (fr) |
IL (1) | IL234485A (fr) |
MX (1) | MX347917B (fr) |
NZ (1) | NZ630719A (fr) |
RU (1) | RU2014140739A (fr) |
SG (1) | SG11201405563VA (fr) |
TW (1) | TW201341385A (fr) |
UY (1) | UY34669A (fr) |
WO (1) | WO2013134219A1 (fr) |
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DK2734205T3 (en) | 2011-07-21 | 2018-06-14 | Tolero Pharmaceuticals Inc | Heterocyclic Protein Kinase Inhibitors |
PT2834243T (pt) | 2012-03-09 | 2018-08-01 | Lexicon Pharmaceuticals Inc | Compostos à base de pirazolo[1,5-a]pirimidina, composições que os compreendem e métodos para a sua utilização |
US8901305B2 (en) | 2012-07-31 | 2014-12-02 | Bristol-Myers Squibb Company | Aryl lactam kinase inhibitors |
JP2016509066A (ja) | 2013-02-22 | 2016-03-24 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | アダプター関連キナーゼ1(aak1)の阻害剤としての5h−クロメノ[3,4−c]ピリジン |
AR097543A1 (es) * | 2013-09-06 | 2016-03-23 | Lexicon Pharmaceuticals Inc | COMPUESTOS BASADOS EN IMIDAZO[1,2-b]PIRIDAZINA, COMPOSICIONES QUE LOS COMPRENDEN Y SUS MÉTODOS DE USO |
JP6473146B2 (ja) | 2013-10-11 | 2019-02-20 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | ピロロトリアジンキナーゼ阻害剤 |
JP6458038B2 (ja) * | 2013-12-10 | 2019-01-23 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | IL−12、IL−23および/またはIFNα応答のモジュレーターとして有用なイミダゾピリダジン化合物 |
RS65417B1 (sr) * | 2014-01-24 | 2024-05-31 | Turning Point Therapeutics Inc | Diaril makrocikli kao modulatori protein kinaza |
US9932320B2 (en) * | 2014-01-31 | 2018-04-03 | Bristol-Myers Squibb Company | Quinoline-based kinase inhibitors |
TW201620911A (zh) * | 2014-03-17 | 2016-06-16 | 雷西肯製藥股份有限公司 | 銜接子關聯激酶1之抑制劑、包含其之組成物、及其使用方法 |
EP3200797A1 (fr) * | 2014-09-30 | 2017-08-09 | Bristol-Myers Squibb Company | Inhibiteurs de kinases à base de quinazoline |
EP3215510B1 (fr) | 2014-11-06 | 2023-06-07 | Bial-R&D Investments, S.A. | Imidazo[1,5-a]pyrimidines substituées et leur utilisation dans le traitement de troubles médicaux |
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WO2016073895A1 (fr) | 2014-11-06 | 2016-05-12 | Lysosomal Therapeutics Inc. | Pyrazolo(1,5-a)pyrimidines substituées et leur utilisation dans le traitement de troubles médicaux |
EP3292124B1 (fr) | 2015-04-10 | 2019-05-22 | Bristol-Myers Squibb Company | Composés de 6h-isochromeno[3,4-c]pyridines et benzo[c][1,7]naphthyridin-6-(5h)-ones en tant qu'inhibiteurs de la kinase 1 associée à un adaptateur (aak1) |
WO2017004342A1 (fr) | 2015-07-02 | 2017-01-05 | Tp Therapeutics, Inc. | Macrocycles de diaryle chiraux à utiliser en tant que modulateurs de protéines kinases |
CN108026108B (zh) | 2015-07-06 | 2021-06-22 | 特普医药公司 | 二芳基大环多晶型物 |
DK3325488T3 (da) * | 2015-07-21 | 2020-09-14 | Turning Point Therapeutics Inc | Chiral diaryl-makrocyklus og anvendelse deraf til behandling af cancer |
JP6843135B2 (ja) * | 2015-11-18 | 2021-03-17 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | IL−12、IL−23および/またはIFNα応答のモジュレーターとして有用なイミダゾピリダジン化合物 |
CA3020310A1 (fr) | 2016-04-06 | 2017-10-12 | Lysosomal Therapeutics Inc. | Composes pyrrolo[1,2-a]pyrimidinyl carboxamide et leur utilisation dans le traitement de troubles medicaux |
CA3020305A1 (fr) | 2016-04-06 | 2017-10-12 | Lysosomal Therapeutics Inc. | Composes imidazo [1,5-a]pyrimidinyl carboxamide et leur utilisation dans le traitement de troubles medicaux |
EP3440080A4 (fr) | 2016-04-06 | 2020-01-22 | Lysosomal Therapeutics Inc. | Composés de pyrazolo[1,5-a]pyrimidinyl carboxamide et leur utilisation dans le traitement de troubles médicaux |
DK3442977T3 (da) * | 2016-04-15 | 2023-10-09 | Blueprint Medicines Corp | Inhibitorer af activinreceptorlignende kinase |
WO2017192931A1 (fr) | 2016-05-05 | 2017-11-09 | Lysosomal Therapeutics Inc. | Imidazo[1,2-a]pyridines substituées, imidazo[1,2-a]pyrazines substituées, composés apparentés et leur utilisation dans le traitement de troubles médicaux |
CN109311902B (zh) | 2016-05-05 | 2022-07-15 | Bial研发投资股份有限公司 | 取代的咪唑并[1,2-b]哒嗪、咪唑并[1,5-b]哒嗪、相关化合物及其用途 |
SG11201900163PA (en) | 2016-07-28 | 2019-02-27 | Tp Therapeutics Inc | Macrocycle kinase inhibitors |
GB201617758D0 (en) | 2016-10-20 | 2016-12-07 | Almac Discovery Limited | Pharmaceutical compounds |
TWI808958B (zh) | 2017-01-25 | 2023-07-21 | 美商特普醫葯公司 | 涉及二芳基巨環化合物之組合療法 |
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CN107082828B (zh) * | 2017-05-19 | 2019-09-17 | 暨南大学 | 一种活性氧响应性高分子载体及其制备方法 |
IL271964B1 (en) | 2017-07-28 | 2024-08-01 | Turning Point Therapeutics Inc | Macrocyclic compounds and their uses |
US10899733B2 (en) | 2017-08-23 | 2021-01-26 | Oregon Health & Science University | Inhibitors of PARPs that catalyze mono-ADP-ribosylation |
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WO2020167990A1 (fr) | 2019-02-12 | 2020-08-20 | Tolero Pharmaceuticals, Inc. | Formulations comprenant des inhibiteurs de protéine kinase hétérocycliques |
CN110684028B (zh) * | 2019-10-28 | 2021-10-26 | 上海阿拉丁生化科技股份有限公司 | 一种2,6-二氮杂双环[3,3,0]辛烷类化合物的制备方法 |
WO2021216757A1 (fr) * | 2020-04-21 | 2021-10-28 | The Uab Research Foundation | Inhibiteurs de la multimérisation de protéine de liaison à l'arn et leurs procédés d'utilisation |
KR102590444B1 (ko) * | 2020-10-16 | 2023-10-18 | 김홍렬 | Pmca 억제제를 포함하는 코로나바이러스 감염 또는 감염 질환의 치료용 조성물 |
KR102590438B1 (ko) * | 2020-10-16 | 2023-10-18 | 김홍렬 | Pmca 억제제를 포함하는 코로나바이러스 감염 또는 감염 질환의 예방 또는 소독용 조성물 |
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US5464764A (en) | 1989-08-22 | 1995-11-07 | University Of Utah Research Foundation | Positive-negative selection methods and vectors |
WO1993004169A1 (fr) | 1991-08-20 | 1993-03-04 | Genpharm International, Inc. | Ciblage de genes dans des cellules animales au moyen de produits de synthese d'adn isogeniques |
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US20070078136A1 (en) * | 2005-09-22 | 2007-04-05 | Bristol-Myers Squibb Company | Fused heterocyclic compounds useful as kinase modulators |
WO2008030579A2 (fr) * | 2006-09-07 | 2008-03-13 | Biogen Idec Ma Inc. | Modulateurs de la kinase associée au récepteur de l'interleukine-1 |
CA2667962A1 (fr) * | 2006-10-30 | 2008-05-08 | Novartis Ag | Composes heterocycliques en tant qu'agents anti-inflammatoires |
FR2934994B1 (fr) * | 2008-08-12 | 2010-09-17 | Sanofi Aventis | Derives de 2-alkyl-6cycloamino-3-(pyridin-4-yl)imidaz°1,2-b! pyridazine, leur preparation et leur application en therapeutique |
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EP2822555B1 (fr) * | 2012-03-09 | 2017-11-08 | Lexicon Pharmaceuticals, Inc. | Inhibition de la kinase 1 associée à un adaptateur pour le traitement de la douleur |
PT2834243T (pt) | 2012-03-09 | 2018-08-01 | Lexicon Pharmaceuticals Inc | Compostos à base de pirazolo[1,5-a]pirimidina, composições que os compreendem e métodos para a sua utilização |
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CN104470523B (zh) | 2017-07-11 |
ES2676826T3 (es) | 2018-07-25 |
KR102085121B1 (ko) | 2020-03-05 |
EP2822559A1 (fr) | 2015-01-14 |
CA2866164A1 (fr) | 2013-09-12 |
BR112014022271A2 (fr) | 2017-06-20 |
IL234485A (en) | 2017-02-28 |
US20160024093A1 (en) | 2016-01-28 |
JP2015509534A (ja) | 2015-03-30 |
MX347917B (es) | 2017-05-17 |
BR112014022271B1 (pt) | 2021-09-21 |
TW201341385A (zh) | 2013-10-16 |
EP2822559B1 (fr) | 2018-05-02 |
CN104470523A (zh) | 2015-03-25 |
WO2013134219A1 (fr) | 2013-09-12 |
NZ630719A (en) | 2017-01-27 |
US20170057964A1 (en) | 2017-03-02 |
HK1203407A1 (en) | 2015-10-30 |
MX2014010584A (es) | 2014-09-18 |
CA2866164C (fr) | 2020-07-07 |
RU2014140739A (ru) | 2016-04-27 |
US8969565B2 (en) | 2015-03-03 |
AU2013230119A1 (en) | 2014-09-25 |
AR090291A1 (es) | 2014-11-05 |
SG11201405563VA (en) | 2014-10-30 |
ZA201406148B (en) | 2016-06-29 |
KR20140138865A (ko) | 2014-12-04 |
UY34669A (es) | 2013-10-31 |
US20130245021A1 (en) | 2013-09-19 |
AU2013230119B2 (en) | 2017-02-23 |
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